Impact of Prior Therapies on Imetelstat Efficacy in Lower-Risk MDS with Transfusion Dependence

Overview

This post hoc analysis of pooled IMerge study data (N=226) evaluated how previous treatments affect imetelstat efficacy in patients with transfusion-dependent, ESA-relapsed/refractory or -ineligible lower-risk myelodysplastic syndromes (LR-MDS). Imetelstat demonstrated clinically meaningful transfusion independence and hemoglobin improvements across most prior treatment subgroups, except those with prior hypomethylating agent (HMA) exposure, where activity was limited.

Background

Lower-risk myelodysplastic syndromes are characterized by ineffective hematopoiesis leading to anemia and chronic red blood cell transfusion dependence, which worsens prognosis. First-line treatments typically include erythropoiesis-stimulating agents (ESAs), luspatercept, or lenalidomide depending on disease subtype and patient factors. Imetelstat, a telomerase inhibitor, recently gained regulatory approval for LR-MDS patients with RBC transfusion dependence who are relapsed, refractory, or ineligible for ESAs. Understanding how prior therapies influence imetelstat response is critical for optimizing treatment sequencing in this chronic disease.

Data Highlights

Key Findings

• Median duration of ≥8-week RBC transfusion independence (TI) in the pooled population was 55 weeks (95% CI: 42–70).
• Among ESA-ineligible patients, 36% achieved ≥8-week RBC-TI, with higher rates (54%) in treatment-naive ESA-ineligible patients.
• Imetelstat showed clinically meaningful RBC-TI and hemoglobin improvements after prior ESA, luspatercept, and lenalidomide therapies.
• Patients with prior hypomethylating agent (HMA) exposure exhibited limited response to imetelstat.
• Patients who had received all four prior therapies (HMA, ESA, lenalidomide, luspatercept) still demonstrated some response, with 33% achieving ≥8-week RBC-TI.

Clinical Implications

Imetelstat offers a valuable treatment option for LR-MDS patients with RBC transfusion dependence, including those previously treated with ESAs, luspatercept, or lenalidomide. Limited efficacy after prior HMA exposure suggests the need for careful patient selection and sequencing of therapies. These findings support considering imetelstat earlier in the treatment course for eligible patients to maximize clinical benefit.

Conclusion

Prior therapies influence imetelstat efficacy in LR-MDS, with robust activity observed after common first-line treatments but reduced response following HMAs. Imetelstat represents an effective therapeutic option for transfusion-dependent LR-MDS patients relapsed, refractory, or ineligible for ESAs.

References

1. IMerge Study Publications and Supplementary Data 2024 -- Impact of Previous Treatments on Imetelstat Efficacy in LR-MDS